The World Health Organization (WHO) recommends rapid intravenous rehydration, using fluid volumes of 70-100mls/kg over 3–6 h, with some of the initial volume given rapidly as initial fluid boluses to treat hypovolaemic shock for children with acute gastroenteritis (AGE) and severe dehydration.
Trang 1R E S E A R C H A R T I C L E Open Access
Rapid intravenous rehydration of children
with acute gastroenteritis and dehydration:
a systematic review and meta-analysis
M A Iro1, T Sell1, N Brown2,3and K Maitland4,5*
Abstract
Background: The World Health Organization (WHO) recommends rapid intravenous rehydration, using fluid
volumes of 70-100mls/kg over 3–6 h, with some of the initial volume given rapidly as initial fluid boluses to treat hypovolaemic shock for children with acute gastroenteritis (AGE) and severe dehydration The evidence supporting the safety and efficacy of rapid versus slower rehydration remains uncertain
Methods: We conducted a systematic review of randomised controlled trials (RCTs) on 11th of May 2017
comparing different rates of intravenous fluid therapy in children with AGE and moderate or severe dehydration, using standard search terms Two authors independently assessed trial quality and extracted data Non-RCTs and non-English articles were excluded The primary endpoint was mortality and secondary endpoints included adverse events (safety) and treatment efficacy
Main results: Of the 1390 studies initially identified, 18 were assessed for eligibility Of these, 3 studies (n = 464) fulfilled a priori criteria for inclusion; most studied children with moderate dehydration and none were conducted
in resource-poor settings Volumes and rates of fluid replacement varied from 20 to 60 ml/kg given over 1-2 h (fast) versus 2-4 h (slow) There was substantial heterogeneity in methodology between the studies with only one
adjudicated to be of high quality There were no deaths in any study Safety endpoints only identified oedema (n = 6) and dysnatraemia (n = 2) Pooled analysis showed no significant difference between the rapid and slow
intravenous rehydration groups for the proportion of treatment failures (N = 468): pooled RR 1.30 (95% CI: 0.87, 1.93) and the readmission rates (N = 439): pooled RR 1.39 (95% CI: 0.68, 2.85)
Conclusions: Despite wide implementation of WHO Plan C guideline for severe AGE, we found no clinical
evaluation in resource-limited settings, and only limited evaluation of the rate and volume of rehydration in other parts of the world Recent concerns over aggressive fluid expansion warrants further research to inform guidelines
on rates of intravenous rehydration therapy for severe AGE
Keywords: Acute gastroenteritis, Dehydration, Intravenous rehydration, Systematic review, Emergency care, Africa, Asia
Background
The global health burden of acute gastroenteritis (AGE)
is substantial Worldwide, 1·73 billion episodes of
diar-rhoea (of which 36 million progressed to severe
epi-sodes) were reported in 2010 in children under 5 years
[1] In this age group, AGE is the single largest cause of
mortality after acute respiratory illnesses resulting in ap-proximately 700, 000 deaths annually year [1], the vast majority occurring in sub-Saharan Africa and South Asia [2, 3] Preventative measures including clean drinking water and improvement in sanitation and rotavirus vac-cination have led to some decrease in the incidence In addition, there has been a modest improvement in case management and outcomes in resource-limited settings
as a result of the use of oral rehydration therapy and the introduction of adjunctive oral zinc treatment to stand-ard management [4, 5] Nevertheless, mortality from
* Correspondence: K.maitland@imperial.ac.uk
4
Department of Paediatrics, Faculty of Medicine, Wellcome Trust Centre for
Clinical Tropical Medicine, Imperial College, W2 1PG, London, UK
5 Clinical Trials Facility, KEMRI Wellcome Trust Research Programme, PO Box
230, Kilifi, Kenya
Full list of author information is available at the end of the article
© The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 2AGE remains unacceptably high A recent large
case-control study of moderate to severe acute gastroenteritis
conducted in four centres in Africa and three centres in
Asia (Global Enteric Multicentre study‘GEMS’) showed
that the odds of dying during a 90-day follow-up period
was 8·5-fold higher in patients with moderate-to-severe
AGE than in non-AGE controls [3] One quarter of
fatal-ities occurred within 7 days during the primary
diar-rhoeal health care encounter indicating that current
management recommendations warrant re-appraisal
For children with moderate to severe AGE,
rehydra-tion with oral or intravenous isotonic fluids to correct
fluid and electrolyte deficits and on-going losses is the
mainstay of treatment Where oral rehydration is not
feasible, rehydration by nasogastric tube is the preferred
option and recommended before intravenous
rehydra-tion in some guidelines [6] However, some aspects of
current management recommendations are controversial
[7] First, the decision to treat with either oral or
intra-venous fluids is largely based upon an assessment of
level of dehydration, which has been shown to be
notori-ously unreliable [8,9] Second, though the evidence
sup-porting the recommendations are scanty, current World
Health Organization (WHO) guidelines for the
treat-ment of severe dehydration (‘Plan C’) are based on rapid,
intravenous administration of isotonic fluids Plan C
rec-ommends a minimum of 100mls/kg, the equivalent
vol-ume replacement for losses in those with 10%
dehydration Plan C is given in two stages over 3–6 h,
dependent on age Recommending an initial 30 ml/kg to
be administrated rapidly (30–60 min) and the remaining
70 ml/kg more slowly over 2.5–5 h respecitvely in
in-fants aged under 12 months and older [10] For those
with hypovolaemic shock initial management
recom-mends fluid boluses (of up to 60 ml/kg) rehydration for
children which is followed by step 2 of plan C (70 ml/kg
more slowly over 2.5–5 h) Whilst the aggressive regime
may be appropriate for cholera, the only infective cause
of secretory-diarrhoea (leading to excess fluid and
elec-trolyte loss), it may not be generalisable to non-cholera
AGE, the dominant cause of AGE worldwide [3] Despite
lack of formal testing, the WHO expert review group
in-dicated this as a strong recommendation [11]
There are, however, increasing concerns over the
safety of rapid intravenous correction of fluid deficits
The only controlled trial (FEAST) assessing fluid bolus
therapy in children with presumed sepsis in sub-Saharan
Africa demonstrated a significantly higher mortality in
those children receiving fluid-bolus therapy [12],
includ-ing a large group with severe dehydration [13] Although
the FEAST trial raises important questions about the
safety of rapid intravenous fluid therapy in severe febrile
illnesses, children with severe dehydration secondary to
AGE were not included in the trial, therefore it is
uncertain whether rapid fluid replacement to correct de-hydration, the cornerstone of standard management in this condition, is safe We therefore conducted a system-atic review of the evidence underpinning current guide-lines for intravenous rehydration
Objectives
To conduct a critical appraisal of available evidence on the safety and efficacy of the rapidity of intravenous fluid therapy for the correction of moderate-severe dehydra-tion in children with AGE
Methods
We did not publish a protocol prior to conducting this review We registered our search strategies on PROS-PERO on 21st May 2017 (review number 67532) We used pre-defined rules relating to eligibility criteria, in-formation sources to be searched, study selection, data collection process, and assessment of risk of bias in identified studies
Selection criteria and process Population
Children aged 0 to 18 years with a diagnosis of acute gastroenteritis and moderate or severe dehydration Due
to the possible variation in the diagnosis of acute gastro-enteritis, where this was not clearly defined in the manu-script, we planned to use either the ESPGHAN [6] or WHO [10] definition for acute gastroenteritis Where the level of dehydration in trial participants was not clearly defined we used the WHO guideline definition for moderate and severe dehydration [6] We excluded studies with severe malnutrition and chronic or persist-ent diarrhoea according to WHO definitions (i.e lasting
≥14 days)
Intervention
Interventions included any form of intravenous rehydra-tion with isotonic solurehydra-tions e.g 0.9% sodium chloride or Ringer’s lactate for rehydration Studies that involved the use of hypotonic solutions were excluded since these are not recommended for intravenous rehydration
Comparison
A comparator was considered as any of the above intra-venous isotonic solution given at different rates for rehy-dration Enteral therapies were not considered
Outcomes
Our primary outcome of interest was mortality Second-ary endpoints included treatment efficacy (as defined in the study protocols - see below) and safety outcomes (within 28 days of rehydration) These included:
Trang 3Proportion of participants with a pre-defined serious
adverse event (other than death) Where this was not
clear we used the definition from the International
Conference on Harmonisation (ICH) Harmonised
Tripartite Guideline [14]: any adverse event is
life-threatening, or requires hospitalisation or prolongation
of hospital stay, results in persistent or significant
disability/incapacity Pre-specified SAEs were new
onset seizures, pulmonary oedema, cerebral oedema
and cardiac failure
4–6 h after the initiation of intravenous rehydration
Dysnatraemia was defined as a serum sodium level
outside the normal range (135-145 mmol/L) [15]
Where dysnatraemia was present at enrolment, we
planned to compare the magnitude (percentage) of
decrease or increase in serum sodium levels from
baseline at enrolment
Efficacy (secondary) outcomes
categorised data Any definition of ‘successful
rehydration’ pre-specified in the manuscript based
on clinical parameters such as (but not restricted to)
weight gain, improved urinary output, increased skin
turgor, improved level of consciousness and able to
keep down oral fluids was acceptable
Length of hospital stay either as continuous or
categorised data
continuous or categorised data
Treatment failure using any criteria defined in the
manuscript
Study type
We included only randomised controlled trials (RCTs)
Search methods for identification of studies
Electronic searches
A comprehensive literature search (Additional file 1:
Table S1a and S1b) of the following databases was
con-ducted on the 11th of May 2017 using a search strategy
developed by a research librarian:
(SCI-EXPANDED); and Conference Proceedings Citation
Index-Science (CPCI-S) (Web of Science)
of 12, May 2017)
(Issue 4 of 12, April 2017)
(Issue 2 of 4, April 2015)
ClinicalTrials.gov(http://clinicaltrials.gov) (last accessed in May 2017)
International Clinical Trials Registry Portal (ICTRP) search portal (http://apps.who.int/trialsearch/)
We performed a visual scan of reference lists of relevant studies and a Google search for additional studies We limited our search to trials published in English language No restriction was placed on year
of publication
Selection of studies
Two reviewers (MI, TS) independently screened the re-sults of the literature search and assessed the eligibility
of studies to be included Level 1 screening involved a broad screen of study titles and abstracts Level 2 screening entailed a comprehensive assessment of the full text of studies that meet the inclusion criteria, or in cases where a definite decision could not be made based
on the title and/or abstract alone We compared mul-tiple reports of the same study, and selected the most comprehensive report Duplicates were excluded Rele-vant data relating to the Population, Intervention, Com-parison, Outcome, Study design (PICOS) criteria were extracted using a pre-agreed data extraction sheet
Assessment of bias in the included studies
The reviewers (MI and TS) assessed the risk bias of each randomised controlled trial using‘The Cochrane Collab-oration’s tool for assessing the risk of bias [16] to evalu-ate internal validity in terms of: i) selection (sequence generation and allocation concealment); (ii) performance and detection (blinding of participants, personnel, and outcome assessors); (iii) attrition (incomplete outcome data) and (iv) reporting (selective outcome reporting)
We used the summary quality assessment at the analysis stage to interpret the results For each domain and for the summary a, we assigned the risk of bias categories as: (i)‘low risk’; (ii) ‘unclear risk’ and (iii) ‘high risk’ [17]
We rated a study as being of good methodological qual-ity when the level of bias was low in all four domains, or
of lower quality when the level of bias was high in at least one of the four domains
Trang 4Assessment of heterogeneity
We assessed statistical heterogeneity by visually inspecting
Forrest plots and using the chi-squared test for
heterogen-eity (with aP value < 0.10 for significance) and the I2
stat-istic as a measure of inconsistency across studies [16]
Data synthesis
We aimed to generate pooled estimates using a
fixed-effect model meta-analysis where trials were judged to
be sufficiently statistically homogenous (I2< 50%) and a
random-effects model where we found significant
het-erogeneity (I2> 50%)
Statistical analysis and summary measures
We carried out statistical analyses using Review Manager
2014 For dichotomous data, we report on relative risk (RR)
with 95% confidence intervals (CIs) For continuous data,
we planned to use weighted mean difference (WMD)
Results
Study selection
The process of study identification was shown in Fig.1
The search identified 1390 studies− 1155 and 235 in the
initial and updated search respectively (Additional file1: Table S1a and S1b) Of the total number identified, 586 were duplicates and therefore were excluded A total of
786 articles were excluded at Level 1 screening since the title and/or abstracts did not suggest that the report related to a trial of rapid intravenous rehydration in chil-dren with acute gastroenteritis We identified 18 RCTS involving intravenous treatment in children with AGE and reviewed the full text of each Only 3 studies were eligible to be included in this review
Included studies
All the eligible RCTs [18–20] were identified through the database search Two of the included studies [18,19] were conducted in resource-rich countries Canada and the USA respectively While the third [20] was conducted in Iran The characteristics of the included studies are sum-marised in Table1 Freedman’s study was conducted in a Paediatric ED in Toronto and enrolled children from 3 to
11 months who were dehydrated as a result of AGE and
in whom oral rehydration had not been feasible Out-comes were defined by a validated dehydration score There were no protocol deviations noted Nager enrolled
Fig 1 Flow diagram for selection of randomised trials and reasons for study exclusion Footnote CRCT = Cochrane Register of Clinical Trials
Trang 5children from 3 to 36 months in Los Angeles and rando-mised to‘ultra rapid’ 50 ml/kg rehydration over 1 h (inter-vention) or ‘standard’ /control 50 ml/kg over 3 h There was a 95% completion rate Azarfar enrolled children in Tabriz, Iran with gastroenteritis unable to tolerate oral fluids They were randomised to 20–30 ml/kg over 2 h (intervention) or 24 h (control) and primarily compared
by proportion in whom vomiting ceased
Excluded studies
Fifteen studies of intravenous rehydration in AGE were excluded (Additional file 1: Table S2) Seven of these compared different routes of fluid administration (en-teral versus paren(en-teral) while eight compared different types of intravenous fluids not rates of fluid administra-tion, and therefore failed to meet our eligibility criteria One unpublished study of slow versus rapid rehydration
in severely malnourished children was identified through
eligibility criteria No studies were excluded because the trial participants did not meet the ESPGHAN/WHO definitions for acute gastroenteritis or the WHO defin-ition for moderate or severe dehydration
Table 1 Characteristics of included studies
Freedman 2011 [ 18 ]
Methods Randomised controlled trial conducted in the emergency
department of the Hospital for Sick Children, Toronto,
Canada Study period between December 2006 and
April 2010
Study aim To determine if rapid rather than standard intravenous
rehydration results in improved hydration and clinical
outcomes when administered to children with
gastroenteritis.
Participants Inclusion criteria: Age > 90 days; diagnosis of dehydration
secondary to gastroenteritis and refractory to oral
rehydration.
Exclusion criteria: children weighing < 5 kg or > 33 kg,
requiring for fluid restriction, had a suspected surgical
condition, had a history of a severe chronic systemic
disease, abdominal surgery, or bilious vomit, had
hypotension, hypoglycaemia or hyperglycaemia,
insurmountable language barrier or lack of telephone
for follow up call.
Interventions One hundred and twelve infants received 60 mL/kg
of 0.9% saline over 60 min (rapid rehydration) and 114
children received 20 mL/kg over 60 min (standard
rehydration).
Allocation 1:1
Outcomes Primary: Rehydration defined as a score on the clinical
dehydration scale of ≤1 two hours after the start of
treatment.
Secondary: Prolonged treatment – a composite measure
defined as admission to an inpatient unit at the index
visit or admission within 72 h of randomisation or a stay
in the emergency department longer than 6 h after the
start of treatment; score on a clinical dehydration scale;
adequate oral fluid intake defined as consuming at
least 5 mL/kg of liquid per 2 h time period; time to
discharge defined as time between start of treatment
and discharge from the emergency department of
inpatient unit; repeat emergency department visit
within 72 h; and attending physician ’s comfort with
discharge at two and four hours, reported on a 5-point
Likert scale.
Nager 2008 [ 19 ]
Methods Pilot randomised controlled convenience sample study in
the emergency department of the Children Hospital in
Los Angeles, USA
Study aim To provide some evidence for our belief that the ultra
protocol could be performed effectively with similar
results as the standard hydrating method.
Participants Ninety-two children aged 3 to 36 months
Inclusion criteria: acute (< 7 days) complaints of vomiting
and/or diarrhoea) and moderate dehydration and failure
of oral rehydration.
Exclusion criteria: severe dehydration, shock, suspected
intussusception, appendicitis, mal-rotation, recent trauma,
meningitis, or congestive heart failure or if any of these
diagnoses appeared as the study progressed; chronic
disease or significant laboratory abnormality including
Na < 130 or > 150 mmol/L and/or K < 3.2 or > 5.5
mmol/L.
Table 1 Characteristics of included studies (Continued)
Interventions 50 mL/kg of normal saline IV administered for 1 h (ultra
rapid IV hydration) or 50 mL/kg normal saline IV for 3 h (standard hydration)
Allocation 1:1 Outcomes Efficacy of treatment by assessing Success and timing of
rehydration, study failures (defined as requirement for admission), output (urine, emesis, stool) during the treatment phase, pre- and post treatment laboratory abnormalities, number of return visits, and whether serious complications occurred.
Azarfar 2014 [ 20 ] Methods Randomised controlled trial conducted in the emergency
department in a tertiary centre (Tabriz children ’s hospital)
in Tabriz, North-West of Iran.
Objective To evaluate the effect of rapid intra- venous rehydration
to resolve vomiting in children with acute gastroenteritis Participants Inclusion criteria: 150 Children with moderate
dehydration or vomiting due to gastroenteritis who had not responded to oral rehydration therapy Exclusion criteria: severe dehydration, shock, and hypotension, electrolyte abnormalities, none or mild dehydration.
Intervention 20-30 mL/kg of a crystalloid solution over either 2 h
(intervention group) or 24 h (control group).
Allocation 1:1 Outcomes Primary outcome: Resolution of vomiting in children
receiving rapid intravenous rehydration.
No secondary outcomes.
Trang 6Risk of bias within studies
Only one study [18] was rated as having low risk of bias
while the other two studies [19,20] were rated as being
of lower methodological quality The risk of bias
assess-ment for all 3 included studies is shown in Fig.2aand b
and Additional file1: Table S3
Results of included studies
There was significant heterogeneity in the design and
outcomes measured in all 3 studies We report on the
results of individual studies and these are organised
using the pre-specified primary and secondary
out-comes for this review
(a) Primary outcome
There were no deaths in any of the studies
(b)Secondary, safety outcomes
We found no reports of any of our pre-specified safety outcomes of interest (new onset seizures, pulmonary oedema, cerebral oedema and cardiac failure) Following
4 h of fluid replacement [18] (n = 226) found that serum sodium levels were similar for both groups (rapid versus standard): 138 mmol/l (2.0) vs 137.5 (2.0);p = 0.06 with only one child per group developing a decrease in serum sodium concentration The magnitude of this decrease was 5.8% (138 mmol/L to 130 mmol/L) in the rapid re-hydration group compared to 1.5% decline (130 mmol/L
to 128 mmol/L) in the standard rehydration group In addition, 1/114 (0.9%) vs 1/112 (0.9%) (rapid versus standard rehydration group) developed an interstitial displacement of the intravenous catheter resulting in ex-travasation [18]
Fig 2 a Risk of bias summary: authors ’ judgements for each included study b Risk of bias graph: authors’ judgements presented as percentages for all studies
Trang 7(b) Efficacy, secondary outcomes
(i) Pre-specified efficacy outcomes of interest reported
Freedman[18]: 41/114 (36%) of children (rapid
tion group) versus 33/112 (29%) in the standard
rehydra-tion group were considered as rehydrated at 2 h after
commencement of rehydration therapy (absolute
differ-ence for rapid vs standard 6.5%, 95% CI− 5.7% to 18.7%;
p = 0.32) Prolongation of treatment was reported in 59/
114 (52%) of the rapid rehydration group and 48/112
(43%) in the standard group (absolute difference for rapid
vs standard, 8.9%, 21.0% to − 5.0%; P = 0.19) More
chil-dren in the rapid intravenous rehydration group were
ad-mitted to hospital at the index visit (33 vs 19, p = 0.04)
with this difference persisting following exclusion of
chil-dren admitted to hospital because of their metabolic
acid-osis [number needed to harm = 9, 95% CI (4 to 57)]
Nager [19]: Treatment failure necessitating admission
was reported in 1/46 (2%) of children of the ultra-rapid
re-hydration group versus 3/46 (6.5%) in the standard group
Overall, 13/88 (14.8%) of 88 subjects returned following
discharge: 7/45 (15.6%) ultra-rapid (CI, 6.5%–29.5%) and
6/43 (14.0%) standard (CI, 5.3%–28.0%), p = 0.999
Azarfar [20]: At two hours following commencement
of intravenous fluid therapy, 63/75 (84%) of children
(rapid rehydration group) versus 62/75 (82%) in the
standard group were considered as rehydrated or had
resolved their vomiting and were thus discharged
(p ≥ 0.05) Two subjects in the intervention group and
none in the standard group required readmission
following discharge
None of the included studies reported on mean
dur-ation of diarrhoea as an outcome measure
(ii) Efficacy outcomes reported in the included studies but not pre-specified in this review
Freedman [18]: Change in serum bicarbonate levels (standard deviation) before and after treatment (standard
vs rapid group) was 0.56 (1.9) vs -0.31(2.2) mmol/L,
p = 0.01 There were no significant differences in (i) mean dehydration score (ii) proportion rehydrated at
4 h, (iii) adequacy of oral intake at 2 and 4 h, (iv) phys-ician comfort with discharge at 2 and 4 h
Nager [19]: There was no significant difference in heart rate decrease (p = 0.163), weight gain (p = 0.343), and mean laboratory values of serum potassium, glucose, blood urea nitrogen, creatinine and CO2 measured pre and post rehydration
Azarfar[20]: None
Meta-analysis
For the primary outcome (mortality) and pre-specified safety endpoint there were no events reported Heterogen-eity precluded meta-analysis of the safety endpoints The efficacy outcomes were sufficiently homogenous for pooled analysis and showed no significant difference in the proportion of treatment failures in the rapid versus slow rehydration groups (N = 468): RR 1.30 (95% CI: 0.87, 1.93) (Fig.3a) Similarly, there was no difference in the re-admission rate for both groups (N = 439): RR 1.39 (95% C: 0.68, 2.85) (Fig.3b) Only one study [18] reported time to resolution of dehydration, finding no significant difference between treatment assignment and successful rehydration
by two hours (odds ratio 1.8 (95% CI 0.90–3.5); p = 0.10) None of the studies reported on length of hospital stay
or mean duration of diarrhoea
Fig 3 a Forest Plot: Treatment failure requiring admission during initial visit: rapid/ultra-rapid (experimental) versus slow/standard (control) intravenous rehydration b Readmission following initial discharge: rapid/ultrarapid (experimental) versus slow/standard (control)
intravenous rehydration
Trang 8Data from this review reveals a paucity of clinical trials
to support a robust evidence for the use of rapid
intra-venous rehydration in children with moderate to severe
dehydration due to AGE We identified only three
stud-ies meeting our pre-defined criteria Only one study
in-cluded children with severe dehydration while the other
two studies included only children with moderate
dehy-dration None of the studies evaluated the WHO Plan C
rapid rehydration guideline, recommended for the
man-agement of severe dehydration, and none were
con-ducted in resource-limited settings Each used a different
methodology, rate of rehydration and tools of
assess-ment Albeit heterogenous, the meta-analysis of these
trials did not suggest superiority of rapid or ultra-rapid
over slower rehydration Moreover, the relatively small
number of patients included in the published,
single-centred trials with endpoints primarily focusing on
non-critical indicators of treatment efficacy in the absence of
mortality endpoints limit the generalisability to
resource-poor settings, where mortality remains an
im-portant outcome in this condition
The available data either informing or evaluating
current treatment guidelines present a number of
limita-tions First only one trial [18] was sufficiently powered
to detect any treatment effects In that trial the
esti-mated sample size provided 80% power to detect a 20%
point difference between in the proportion of children
rehydrated after two hours of commencing rehydration
treatment [18] Second, the low quality of the two other
trials [19, 20] precludes conclusions pertaining to safety
and efficacy of current guidelines Finally, all published
trials were conducted in well-resourced emergency
rooms so it is unclear whether the findings would be
ap-plicable to low and middle income countries (LMIC)
which face the bulk of the global burden of AGE
The 2013 version of the WHO pocket book [10]
con-tained no amendments to the original guidelines, and, as
a result, recommendations for fluid management of
AGE are now over a decade old Notable it that the
guidance remains “strongly recommended’ though the
evidence base is reported as weak [11,12]
The FEAST trial, conducted in sub-Saharan Africa,
demonstrated that children randomised to fluid boluses
of either saline or albumin had a 3.3% higher mortality
than children receiving only maintenance fluids [12] A
subsequent sub-analysis showed that whilst there was
evidence of improved short-term hemodynamic effects
with bolus, this did not result in a better outcome with
the excess mortality was due to cardiogenic or shock as
terminal clinical events (n = 123; 4.6% in bolus versus
2.6% in control, P = 0.008) rather than respiratory or
neurological terminal clinical events as anticipated [13]
The trial re-emphasises the importance of testing all
recommendations in which the evidence base is weak Relevant to this review is that children with AGE were not enrolled in FEAST, thus the results cannot be ex-trapolated and therefore further research is required to clarify whether these findings are also relevant to those with diarrhoea-related dehydration A large prospective multicentre observational study in Kenya examining physcians use of resusciation and rehydration fluids with respect to outcome iincluded a large subgroup with se-vere dehydrating diarrhoea [21] Most fluid boluses given for resuscitation of hypovolaemic shock secondary to de-hydration/diarrhoea (94%, 582/622), and case fatality was high in this group (34%, 211/622) Overall mortality was 7.9% (798/10,096) in children with dehydration/diar-rhoea [21]
Though there are some physiological differences be-tween the two illness phenotypes with intracellular dehy-dration the first pathological step in AGE, shock and electrolyte disturbance are common to both This sug-gests, at the very least, that the current WHO guidance
of rapid rehydration should be formally assessed through large phase III RCT with disability-free mortality as the primary endpoint in an appropriate resource limited set-ting A safety and pilot efficacy study (using physio-logical surrogates of efficacy) has been registered on ISRCTN 67518332 aiming to compare the current WHO Plan‘C’ rehydration protocol with a strategy that aims to give a slower rehydration regimen (without fluid bolus) using the same total volume (100 ml/kg of Ringers Lactate) over 8 h, irrespective of age The hypothesis indicates that slower rehydration is equally effective in rehydration but is associated with fewer fluid related adverse effects with a view to informing the de-sign of a future definitive multi-site Phase III trial The strengths of the review include a rigorous search and reporting according to the established PRISMA guidelines Potential weaknesses include the possibility
of undetected unpublished work, inclusion of non-English studies and the heterogeneity in identified stud-ies precluding a formal meta-analysis to augment the systematic review Another review has recently been published with similar conclusions for management of AGE in emergency rooms in high income (HMIC) set-tings [22] However, our review sought to address the global burden of disease and treatment challenges for AGE rehydration and, given the paucity of data, we can only conclude that robust trials are long overdue
Conclusion There is no high quality trial evidence from LMIC to support the current WHO guidance of rapid intravenous rehydration in children with acute gastroenteritis com-plicated by severe dehydration, nor is there relevant
Trang 9evidence from trials in well-resourced settings that
dem-onstrated a favourable benefit of rapid rehydration over
slow rehydration We suggest this dilemma can only be
robustly addressed in future by an adequately powered
randomised trial
Additional file
Additional file 1: sTable 1a Search results (up to October 2014).
sTable 1b Search results (October 2014 to May 2017) sTable 2 Excluded
studies sTable 3 Risk of bias for included studies (DOCX 145 kb)
Abbreviations
AGE: Acute gastroenteritis; CIs: Confidence intervals; ED: Emergency
department; ESPGHAN: European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition; FEAST: Fluid as a supportive therapy; LMIC: Low
and middle-income countries; RR: Relative risk; WHO: World Health
Organization
Acknowledgements
The authors would like to thank Nia Wyn Roberts of the Bodleian Health
Care Libraries, University of Oxford who generated the search terms and
contributed to the Electronic searches section of the protocol and Merryn
Voysey of the Nuffield Department of Primary Care Health Sciences,
University of Oxford who provided some assistance with the statistical
aspects of this paper.
Funding
None
Availability of data and materials
The datasets used and/or analysed during the current study available from
the corresponding author on reasonable request.
Authors ’ contributions
Study conception and design: KM, NB, MAI Screening of studies: MAI, TS.
Data extraction: MAI, TS Drafting of manuscript: MAI Critical revision and
contribution to scientific content: KM, NB, MAI and TS All authors read and
approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Oxford Vaccine Group, Department of Paediatrics and the NIHR Biomedical
Research Centre, University of Oxford, Headington, Oxford OX3 7LE, UK.
2 Department of Paediatrics, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
3 Department of Child Health, Aga Khan University, Karachi, Pakistan.
4
Department of Paediatrics, Faculty of Medicine, Wellcome Trust Centre for
Clinical Tropical Medicine, Imperial College, W2 1PG, London, UK 5 Clinical
Trials Facility, KEMRI Wellcome Trust Research Programme, PO Box 230, Kilifi,
Received: 5 May 2016 Accepted: 23 January 2018
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